A variety of techniques have been developed to non-invasively image human brain function that are central to understanding how the brain works and to detect pathology. Current methods can be broadly divided into those that rely on hemodynamic responses as indicators of neural activity and methods that measure neural activity directly. The approaches all suffer from poor temporal resolution, poor spatial localization, or indirectly measuring neural activity.
The quest for higher spatial and temporal resolution brain imaging is driven by the evidence that knowledge of the structural-functional relationships within the human brain will greatly improve an understanding of brain function. Functional imaging studies provide information about cortical regions that form networks for attentional deployment, while electrophysiological studies have begun to unravel their millisecond-level temporal properties. High temporal resolution functional studies can elucidate oscillatory activity that is thought to structure the flow of information between distributed brain regions or be involved with information encoding and retrieval. Functional neuroimaging is also playing a growing role in human behavioral studies and the understanding of normal and abnormal function. Disease pathophysiology in epilepsy, for example, is dynamic in space and time and electrophysiological studies can provide clinically useful information for evaluating surgical potential in medically intractable partial epilepsy.
Functional magnetic resonance imaging (fMRI) is by far the most prevalent noninvasive functional brain imaging method in use today. Magnetic resonance imaging (MRI) spatially encodes the nuclear magnetic resonance (NMR) signature of nuclei, typically protons, in a volume of interest. The NMR signal arises from a population of spin-polarized nuclei precessing about a “measurement” field, Bm, with a characteristic “Larmor” frequency, ωm=γBm (where γ is the magnetogyric ratio). The NMR signal decays with time (‘free induction decay’ or FID) as transitions between spin states return the population to a Boltzman distribution (longitudal relaxation characterized by decay time T1), and as spins in the population lose phase coherence (transverse relaxation characterized by T2). The observed NMR decay time, T2*, is a combination of these and other effects such as spatiotemporal variations of Bm. Today's high-field (HF) MRI machines employ static magnetic fields in the 1.5 to >9 Tesla (T) range to yield exquisite anatomical resolution. The last decade has also witnessed an explosion in fMRI research and applications that detect hemodynamic (i.e. blood-flow and blood-oxygenation) changes that are thought to be related, albeit indirectly, to neural activity. Furthermore, while neural processes occur on a millisecond timescale, hemodynamic responses vary on the timescale of seconds. Thus, even as fMRI can provide exquisite spatial resolution, it is only an indirect (at best) measure of neural activity with sluggish temporal resolution.
In contrast, magnetoencephalography (MEG) and electroencephalography (EEG) noninvasively measure the magnetic and electric fields generated directly by neural activity. While these modalities yield detailed temporal information (milliseconds or better), the spatial localization must be inferred from spatial modeling priors resulting in the classic ill posed inverse problem of electromagnetism. Thus, while MEG and EEG provide superb temporal resolution, the electrophysiological “imaging” is only “indirect” at best.
Researchers have recently proposed that neuroelectrical activity may interact with a spin-polarized population to cause a measurable phase change in the population, that may enable “direct neural imaging” (DNI) using MRI methods. Several studies have focused on the feasibility of DNI at HF (High Frequency), including those using current phantoms (passing a current through a bolus of water). These studies concluded, based on both modeling and experimental results, that DNI at HF may be possible. While most phantom studies used currents orders of magnitude larger than produced in the brain, one study investigated sources with current dipole equivalent amplitudes of ˜10-100 nA-m, approximately representative of human evoked brain activity. A common problem with all of these studies was the use of effective DC currents while human brain activity is more accurately characterized by waveforms that contain a broad distribution of frequencies with roughly “zero-mean” amplitude over typical MR measurement time windows. Such a time-varying current distribution would have a far smaller effect on the NMR signal than a DC current. In the limiting case of a correlated zero-mean current distribution, the phase effects would integrate to zero resulting in no detectable current-induced difference in the NMR signal. Furthermore, the phantom studies avoided susceptibility artifacts that would otherwise be a significant confound at HF.
The only in vivo experimental measurement of DNI at HF has been vigorously debated in the neuroimaging community. A serious confound for this, or any HF measurement, is the “susceptibility artifact” caused by the different magnetic properties of oxy- and de-oxy hemoglobin—an effect that is orders of magnitude larger than the expected direct neural effect on the NMR signal. Indeed, these susceptibility differences are the basis for fMRI and because they accompany neural activity, they become the greatest impediment to measuring DNI at HF. Furthermore, because human brain activity does not produce DC currents, the expected phase effects would be far smaller than phantom experiments performed to date would lead one to believe.
What is needed is a physical system and new techniques to tomographically image the direct consequences of neural activity. It has been suggested that the NMR phase will be altered by neural activity and imaged by MRI methods. While demonstrating this effect has been elusive, the present inventors now describe how ultra-low field MRI is more sensitive for measuring neural activity. Resonant mechanisms at ultra-low fields can further enhance the effect of neural activity on NMR signals. The observed resonant interactions described in detail herein can form the foundation of a new functional neuroimaging modality capable of high resolution direct neural activity and brain anatomy tomography.